Impact of perioperative COVID-19 infection on postoperative complication in cesarean section using Korean National Health insurance data

The vulnerability during pregnancy has raised concerns about the potential impact of COVID-19 on obstetric anesthesia, an essential aspect of maternal care during cesarean section procedures. To evaluate the influence of COVID-19 infection on obstetric anesthesia during cesarean section, we analyzed the data from Korean National Health Insurance System (NHIS). This retrospective study utilized data from Korean NHIS. We included patients admitted with operation codes specific to cesarean section between January 1, 2020, and December 31, 2021. We classified patients into a COVID (+) group with a diagnosis code (U071) 30 days around surgery and a COVID (−) group without the code in the same period. The primary outcome was 30-day mortality that was defined as death within 30 days of admission due to any causes. Secondary outcomes were pulmonary complications (pneumonia, acute respiratory distress syndrome [ARDS], pulmonary thromboembolism [PTE], or unexpected postoperative mechanical ventilation), ICU admission, cardiac arrest, myocardial infarction [MI], other thromboembolic events, surgical site infection, sepsis, acute renal failure [ARF], and hepatic failure. Among 75,268 patients who underwent cesarean section, 107 had a COVID-19 diagnosis code, while 75,161 did not. After 1:4 propensity score matching (PSM), 535 patients were included in each group. 30-day mortality showed no significant differences between the two groups both before and after PSM. The COVID (+) group demonstrated significantly elevated rates of pneumonia, ARDS, PTE, and surgical site infection both before and after PSM. Hospital length of stay and admission costs were also significantly longer and higher, respectively, in the COVID (+) group before and after PSM. In subgroup analysis, no differences were observed in mortality and postoperative complications based on the anesthesia method after matching. COVID-19 infection is associated with increased rates of postoperative complications, including pneumonia, ARDS, PTE, surgical site infection, longer hospital stays, and increased admission costs, in patients who underwent cesarean section.


Study design
This retrospective study utilized data from the Korean NHIS, a singular mandatory national healthcare institution encompassing nearly the entire Korean population.Citizens are obliged to enroll in the NHIS, and claims submitted for reimbursement undergo review by the Health Insurance Review and Assessment Service.The dataset for our study was extracted from the National Health Information Database (NHID), established by the NHIS.The NHID is a publicly accessible database containing comprehensive information on healthcare utilization, health screenings, sociodemographic variables, and mortality for the entire population of South Korea, spanning the years 2020 to 2021.Access to the NHID is granted to researchers with approved study protocols by the official review committee.
Healthcare claims data, in this context, pertains to information derived from medical care benefit statements submitted by healthcare institutions for reimbursement from the NHIS.This dataset encompasses details on medical institutions, patients' personal information, International Classification of Diseases, 10th revision (ICD-10) codes, medical history (tests, procedures, and surgeries), prescriptions, and associated costs.The National Health Insurance Sharing Service (NHISS), operated by the NHIS, facilitates policy and academic research by providing support through the dissemination of public health information 10 .
For all (customized) data, the provided variables are restricted to the research purpose, with only results corresponding to the research design made available, and raw data remains inaccessible.The concept of data ownership is not applicable, and customized data analysis can be conducted either by visiting analysis centers operated by respective institutions or, in some cases, remotely accessing the data for analysis within private laboratories.National data meeting researcher-specified conditions are accessible to researchers 11 .

Participant
We included all patients who underwent cesarean section in hospitals in Korea between January 1, 2020, and December 31, 2021.The major inclusion criterion was admission with a specific operation code for cesarean section surgery (R4514, R4516, R4517, R4518, R4519, R4520, R4507, R4508, R4509, R4510, R5001, R5002).Patients with a diagnosis of pneumonia within 1 year were excluded.Also, we excluded patients with missing data.

Variables and outcome
Patients were categorized into two groups according to COVID-19 diagnosis code (U071).The COVID (+) group was defined as patients with a COVID-19 diagnosis code (U071) within 30 days before or after surgery.The COVID (−) group consists of patients with no COVID-19 diagnosis code (U071) within 30 days before or after surgery.Demographic characteristics, such as sex, age, region, and economic level were recorded.Additionally, data on COVID-19 vaccination status, diagnosis, surgical procedures, anesthesia methods (general or regional), and American Society of Anesthesiologists (ASA) physical status classification were documented.Information on the length of hospital stay and the type of hospital (clinic, general hospital, tertiary care hospital) was also captured.Other recorded details encompassed admission to the ICU, the duration of ICU stay, and the application of mechanical ventilation.The dataset included emergency surgery status, and complications such as venous thromboembolism, pulmonary thromboembolism (PTE), pneumonia, and acute respiratory distress syndrome (ARDS).Furthermore, the patient's survival status, date of death, cause of death, and comorbid conditions has been included.Comorbidities were assessed using the Charlson Comorbidity Index (CCI) 12 and Elixhauser Comorbidity Score (ECS) 13 , which classify patients' additional health conditions based on ICD diagnosis codes.These methods assign weights to specific comorbidities, reflecting their impact on in-hospital mortality.The

Statistical analysis
We matched perioperative COVID (+) group and COVID (−) group in a 1:4 ratio by propensity score matching (PSM) via the caliper matching method to minimize selection bias and the difference in demographic characteristics and comorbidities between the two groups.The propensity scores, estimated through logistic regression analysis utilizing variables such as age (analyzed as continuous variable), CCI, ASA physical status classification 3 or higher, and comorbidities (hypertension, diabetes, liver and kidney disease) were employed for a greedy 1:4 matching.The standardized mean difference (SMD) was defined as less than 0.1 in absolute value (Supplementary Fig. 1).To enhance the quality of the matching, we used the Logit Propensity Score (LPS) as the matching criterion.The caliper, defined as the allowable tolerance for matching, was set to 0.1 times the standard deviation of the LPS.This caliper setting ensured that matched pairs were sufficiently similar in terms of their propensity scores, thereby improving the comparability of the groups.
In addition, logistic regression models, Chi-square tests, and T-tests were utilized.For the entire surgical cohort, PSM variables included age, gender, and CCI, ensuring that the SMD for all variables was below 0.1.Postmatching results showed 107 COVID (+) patients and 428 COVID (−) patients, totaling 535 surgical patients as the final study cohort.
The normal distribution of variables was evaluated via the Kolmogorov-Smirnov test or Shapiro-Wilk test.For pre-matching data, continuous variables were analyzed using the Wilcoxon rank-sum test, and categorical variables were compared using the Chi-square test or Fisher's exact test.For post-matching, continuous variables were tested using paired t-test or Wilcoxon's signed rank-sum test, and categorical variables were compared with the McNemar test or exact McNemar test.All statistical analyses used were two-sided, and the significance level was set at a P-value less than 0.05.R version 3.4.1 (RStudio, Boston, MA, USA) and SAS Enterprise Guide version 6.1 (SAS Institute Inc., Cary, NC, USA) were used for the statistical analyses.

Results
We identified 75,703 patients who underwent cesarean section and were admitted to the hospital during 2020-2021.Among the total patients, 435 were excluded because a pneumonia diagnosis code was confirmed within 1 year prior to the surgery date.Finally, 75,268 patients were included in our study.Among them, 107 patients had a COVID-19 diagnosis code (U071) within 30 days before or after the surgery, while 75,161 patients did not have a COVID-19 diagnosis code (U071) within the same time frame (Fig. 1).
Table 1 depicts the baseline characteristics before and after PSM.Prior to PSM, baseline characteristics, including comorbid conditions, differed between the COVID (+) and COVID (−) groups.Following 1:4 PSM, 535 patients were included in each group, with no significant differences observed in covariates, including CCI, ASA physical status classification greater than 3, and comorbidities such as hypertension, diabetes, liver, and kidney disease.
Table 2 presents the primary and secondary outcomes before and after the implementation of PSM.The primary outcome, which includes 30-day mortality, exhibited no significant differences between the two groups, both before and after matching.In the postoperative complication category, the COVID (+) group exhibited significantly higher rates of pneumonia, ARDS, PTE, and surgical site infection both before and after PSM.Hospital length of stay and admission costs were also significantly longer and higher, respectively, in the COVID (+) group before and after matching.
Table 3 displays the results of logistic regression analysis examining overall pulmonary complications in the COVID (+) group compared to the matched COVID (−) group.In the COVID (+) group, the adjusted odds ratio (OR) for pulmonary complications was 79.772 with a 95% confidence interval (CI) of 11.059 to 575.44, showing a statistically significant increase (p < 0.001).Additionally, among patients with ASA physical status classification 3 or higher, the adjusted OR for pulmonary complications was 23.453 (95% CI 4.232-129.987,p = 0.0003), demonstrating statistical significance.
In a subgroup analysis of anesthesia methods, there were no differences in 30-day mortality and postoperative complications after matching (Table 4).While pre-matching revealed certain disparities in complications and outcomes, post-matching analysis demonstrates a reduction in these differences, emphasizing the importance of accounting for potential confounding factors when evaluating the impact of anesthesia types on surgical outcomes among COVID (+) and COVID (−) patients.

Discussion
In this study, we investigated the impact of perioperative COVID-19 infection on obstetric anesthesia in patients undergoing cesarean section procedures.Utilizing a comprehensive dataset from the Korean NHIS, our findings shed light on crucial aspects of maternal care during the COVID-19 pandemic.The analysis, including propensity score matching, revealed significant differences in postoperative complications, hospital length of stay, and admission costs between the COVID (+) and COVID (−) groups.Notably, despite matching for various demographic and comorbidity factors, the COVID (+) group exhibited higher rates of pulmonary complications, emphasizing the need for targeted interventions and heightened vigilance during obstetric anesthesia in the context of COVID-19.
For our analysis, we defined the COVID (+) group as patients with a COVID-19 diagnosis code (U071) within 30 days before or after surgery.This definition was informed by CDC research indicating that most patients recover from acute COVID-19 illness within four weeks, allowing us to capture the immediate and short-term effects of the infection on surgical and anesthesia outcomes 15 .Additionally, prior research have shown that patients undergoing surgery within four weeks of a COVID-19 diagnosis have a significantly higher risk of pulmonary complications and increased mortality rates [16][17][18] .Given these considerations and the practical challenges of subdividing our dataset into pre-and post-surgery infections, we adopted a 30-day window to comprehensively evaluate the impact of COVID-19 during this critical period.
According to the pre-matching baseline characteristics in our study, the rate of admissions through the emergency department was 25.234% in the COVID (+) group, compared to 10.556% in the COVID (−) group, indicating more than a two-fold increase.Furthermore, the rates of emergency surgeries and nighttime surgeries were approximately twice as high in the COVID (+) group.Supporting these findings, a retrospective cohort study conducted in Australia reported a 2.3% increase in the emergency cesarean section rate during the COVID-19 pandemic compared to the pre-pandemic period 19 .The CCI in our pre-matching baseline data was significantly higher in the COVID (+) group, indicating a greater burden of comorbidities.Although the prevalence of diabetes was higher in the COVID (+) group at 4.673% compared to 2.129% in the COVID (−) group, this difference did  www.nature.com/scientificreports/with cesarean sections 24 .In contrast, our analysis during the COVID-19 pandemic showed a higher mortality rate of 0.025%.Although an increase in cesarean section-associated maternal mortality was observed during the COVID-19 pandemic, our study did not find a significant difference in mortality between the COVID (+) group and the COVID (−) group.This is likely due to the very low number of mortality cases observed 25 .Including data from the entire pandemic period, up to 2023, might have provided more cases, enhancing the statistical significance.
Prior international studies have reported high cesarean delivery rates among women with SARS-CoV-2 infection.Notably, a nationwide cross-sectional study from Korea 26 found a rate of 78.1%, a case series from China 27 reported 76.9%, and cohort studies from the United Kingdom 28 and Spain 29 observed rates of 59% and 47%, respectively.This observation suggests a significant association between COVID-19 infection during pregnancy and an increased preference for cesarean delivery.In the early stages of the global COVID-19 pandemic (SARS-CoV-2), guidelines endorsed prioritizing regional anesthesia over general anesthesia for cesarean sections in medical practice 30,31 .To minimize the aerosolization of viral particles during endotracheal intubation/extubation and airway manipulation, neuraxial anesthesia is the preferred choice 8 .The COVID-19 pandemic has led to a notable decline in the use of general anesthesia for cesarean sections.In the UK, the rates of general anesthesia for these procedures have decreased significantly 32 .Prior to the pandemic, the rate was 7.5%, which dropped to 3.3% in 2020, representing a significant reduction of 4.2% (95% CI 1.7-6.6;p = 0.0016) (p = 0.0042).Similarly, the group in Israel has reported an increase in the use of neuraxial anesthesia for planned cesarean sections, from 44.8% to 79.3% (p < 0.0001) 33 .A cross-sectional study in the Northwest of England, involving more than 17,000 births during the COVID-19 pandemic, found higher rates of neuraxial anesthesia and a significant reduction in conversions to general anesthesia.General anesthesia rates dropped from 7.7 to 3.7% 34 .Contrastingly, Katz et al. reported that symptomatic SARS-CoV-2-infected patients are more prone to receiving general anesthesia for cesarean delivery (adjusted OR 3.69; 95% CI 1.40-9.74)as a result of maternal respiratory failure 9 .Concerns about performing neuraxial anesthesia in COVID-19-positive parturient may arise due to the potential risk of www.nature.com/scientificreports/systemic infection, even though infectious complications are relatively uncommon.According to a study involving pregnant women with SARS-CoV-2 undergoing cesarean section and cerebrospinal fluid (CSF) analysis during spinal anesthesia, the genomes of SARS-CoV-2 and other neurotropic viruses were not detected in any samples 35 .Therefore, based on these findings, spinal anesthesia was deemed safe for SARS-CoV-2-positive pregnant women with mild disease.In addition, According to a prospective observational study conducted by  36 .Until now, there has been no meaningful study comparing outcomes based on anesthesia methods (general anesthesia vs. neuraxial anesthesia) in cesarean deliveries for mothers infected with COVID-19.In our study, we conducted a subgroup analysis, adjusting for comorbidities, including the CCI, ASA physical status classification greater than 3, and conditions such as hypertension, diabetes, liver, and kidney disease.The results did not reveal significant differences in outcomes based on the chosen anesthesia method.Various confounding factors, such as fetal distress, deterioration of the mother's health, catheter failure, and inappropriate timing of LMWH for regional anesthesia, contribute to the preference for general anesthesia over neuraxial anesthesia, making outcome comparisons challenging 37 .
A hospital-based prospective study conducted at 12 centers across 9 countries reported that emergency caesarean delivery increases the risk of maternal deaths compared to elective cesarean delivery 38 .There is no available data on the mortality comparison between elective and emergency cesarean delivery in COVID-19-infected mothers.In our study, regression analysis revealed an adjusted OR of 22.281 for cases where emergency surgery was performed, with a 95% CI ranging from 1.363 to 364.113.However, the considerable length of the confidence interval suggests a somewhat unstable outcome.This is attributed to the low absolute number of actual mortality cases.
Ensuring the safety of both mother and fetus is paramount in obstetric anesthesia during cesarean section delivery.The challenges posed by COVID-19 in surgical and anesthesia scenarios are concerning, potentially impacting the overall health of both mother and fetus.This study reveals no significant difference in 30-day mortality between COVID-positive and COVID-negative patients, irrespective of the anesthesia type.It suggests that while COVID-19 infection increases the risk of specific complications such as pneumonia, ARDS, PTE, and surgical site infections, it does not directly influence short-term mortality in this context.
These findings offer reassurance to clinicians and pregnant patients facing challenging decisions regarding cesarean delivery amid the pandemic.However, it's crucial to acknowledge that the absence of a difference in short-term mortality does not diminish the increased risk of complications associated with COVID-19.
Given the evolving nature of the COVID-19 pandemic and the emergence of new variants, ongoing research is crucial.Future studies should focus on long-term maternal and fetal outcomes, the effectiveness of different anesthesia techniques in the COVID-19 context, and the impact of vaccination status on surgical and obstetric outcomes.Moreover, research exploring the psychosocial impact of the pandemic on pregnant individuals undergoing cesarean sections would be valuable.
Despite the valuable insights offered by this study, it is crucial to consider several limitations.Firstly, the inherent nature of retrospective claim data, primarily crafted for reimbursement purposes rather than clinical research, needs acknowledgment 39 .Consequently, critical clinical information, such as patients' clinical data or disease severity, is not included in the database.Secondly, the study's findings are based on a specific timeframe (2020-2021), and the dynamics of the pandemic may have evolved since then.Additionally, long-term outcomes beyond 30 days were not assessed, and further research is warranted to explore the potential impact of COVID-19 on maternal and fetal health in the extended postoperative period.Thirdly, due to the limitations of our dataset, we could not distinguish between COVID-19 infections occurring before and after cesarean section, which could have provided more precise insights into the distinct impacts during the acute and recovery phases of the infection.Lastly, the PSM process significantly reduced the sample size, leading to increased variability and wider CIs in the multivariable analysis.In addition, the inability to assess colinearity among the variables may further contribute to these large CIs.Future studies with larger sample sizes and through check for colinearity may help to reduce the variance and provide more stable estimates.

Conclusions
In summary, our study found that COVID-19 infection had little impact on 30-day mortality rates in patients undergoing cesarean section.However, patients with COVID-19 exhibited a significantly higher incidence of postoperative complications, including pneumonia, acute respiratory distress syndrome (ARDS), pulmonary thromboembolism (PTE), surgical site infections, and prolonged hospitalization.The review of outcomes during the COVID-19 pandemic period emphasizes the critical need for increased surveillance and management of pulmonary complications, particularly in patients with pre-existing comorbidities and an ASA score greater than 3. https://doi.org/10.1038/s41598-024-66901-5www.nature.com/scientificreports/

Figure 1 .
Figure 1.Flow diagram of study population.

Table 1 .
Baseline characteristics before and after propensity score matching.Values are expressed as absolute numbers (percentages) or absolute numbers.SMD standardized mean difference, ASA American Society of Anesthesiologists, CVA cerebrovascular accidents.*SMD < 0.1 indicates effective matching between groups.

Table 2 .
Primary and secondary outcomes before and after propensity score matching.Values are expressed as absolute numbers (percentages) or absolute numbers.ARDS acute respiratory distress syndrome, PTE pulmonary thromboembolism, MI myocardial infarction, ARF acute renal failure, ICU intensive care unit, ECMO Extracorporeal Membrane Oxygenation.*p < 0.05 indicates statistically significant differences between groups.

Table 3 .
Logistic regression analysis for overall pulmonary complications in the COVID (+) group compared with the matched COVID (−) group.Values are presented as odds ratio with corresponding 95% confidence intervals.OR odds ratio, CI confidence interval, ASA American Society of Anesthesiologists.